The rising prevalence of obesity and type 2 diabetes threatens to limit human health span and to impose overwhelming economic burdens. New therapeutic approaches are urgently needed. Since the discovery within the last decade of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled respiration. Brown adipocytes are concentrated in discrete depots of brown adipose tissue; whereas, beige adipocytes develop from progenitors within white adipose tissue (WAT) in response to specific stimuli, including cold and ?3-adrenergic receptor agonists. Recent research has revealed key elements of the transcriptional machinery that governs brown/beige cell differentiation, as well as numerous factors that activate brown/beige adipocytes. Importantly, relatively little is known about the intracellular factors that integrate hormonal and environmental signals with the nuclear transcriptional machinery that activates thermogenesis in adipocytes. This project investigates one such factor, Perilipin 5, which was originally discovered as a lipid droplet coat protein expressed in highly oxidative tissues, including brown adipose tissue. Perilipin 5 has been studied primarily as a regulator of lipase access and activity on the lipid droplet. Another function of Perilipin 5 has emerged from the discovery that, following its phosphorylation by protein kinase A, Perilipin 5 boosts gene expression related to oxidative metabolism and to the thermogenic program through physical interaction with SIRT1 and PGC-1? in the nucleus. The underlying hypothesis of this application is that increasing Perilipin 5 in thermogenic adipocytes will sensitize them to activation by stimuli such as cold exposure and ?3-adrenergic receptor agonists and enable effective energy dissipation to address obesity and improve metabolic health. The overall goal of this project is to establish a preclinical model for increasing the capacity of brown/beige adipocytes to dissipate excess energy acquired through overnutrition. Specific Aim 1 will define the physiological role of Perilipin 5 in brown adipose tissue (BAT) thermogenesis and systemic glucose and lipid metabolism in adult mice by means of novel mouse models of inducible, BAT-specific overexpression and knockout of Perilipin 5. Specific Aim 2 will investigate the role of Perilipin 5 in maintaining mitochondrial integrity in BAT during cold stress and will explore the heterogeneity of BAT adipocytes defined by Perilipin expression. Specific Aim 3 will determine whether Perilipin 5 is sufficient to sensitize WAT to beiging in adult mice subjected to physiological (cold exposure) or pharmacological (?3-adrenergic receptor agonist) stimuli, and whether Perilipin 5 is necessary for WAT beiging triggered by these stimuli. Completion of these Aims will establish Perilipin 5 as a critical integrator of hormonal and transcriptional signaling in thermogenic adipocytes and may suggest novel therapeutic strategies to unleash the thermogenic potential of fat cells.